Aortic Denudation Research Articles

Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation.

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been linked to vascular smooth muscle cell (SMC) migration and proliferation leading to atherosclerosis, restenosis, and chronic allograft rejection. This study describes the effect of CGP 53716, a specific PDGFR tyrosine kinase inhibitor on SMC proliferation and migration in vitro and in neointimal formation in vivo. CGP 53716 inhibited dose dependently tyrosine phosphorylation of both the known PDGFRs: the PDGFR-alpha and PDGFR-beta. In primary rat SMC cultures, a dose-dependent inhibition of PDGF-AA and PDGF-BB induced migration, and tritiated thymidine incorporation of SMC was seen at nontoxic concentrations. After rat carotid artery ballooning injury in vivo, the migration of alpha-actin-positive cells on the luminal side of internal elastic lamina was decreased with 50 mg x kg(-1) x day(-1) of CGP 53716 from 38 +/- 10 (control group) to 4 +/- 2 (P<0.0001, Mann-Whitney U test, N=18). CGP 53716 did not inhibit the number of replicating bromodeoxyuridine (BrdU)-incorporating cells in the intima, media, or adventitia during BrdU labeling at 0-96 postoperative h, though it inhibited significantly (P<0.01) the replication of medial and intimal cells from 93 h onward. Intima/media ratio was inhibited by 40% after 14 days in the CGP 53716-treated group (P=0.028) after rat aortic denudation. The results indicate that inhibition of the PDGFR tyrosine kinase inhibits SMC migration and proliferation in vitro, SMC migration, and, to a lesser extent, proliferation after ballooning injury in vivo, confirming a causal role for activation of the PDGFR and the formation of neointimal lesions.

Inhibitory effect of a fullerene derivative, monomalonic acid C 60, on nitric oxide-dependent relaxation of aortic smooth muscle

1. 1. Effects of a fullerene C 60 derivative, monomalonic acid C 60 (MMA C 60), on endothe-lium-containing or denuded aorta of rabbit, trachea and ileum of guinea pig, and stomach (fundus), vas deferens and uterus of rat were studied pharmacologically. 2. 2. MMA C 60 (10 −5 M) significantly reduced the maximum response of the relaxation induced by acetylcholine in endothelium-containing thoracic aorta of rabbit, and the acetylcholine-induced relaxation was recovered in the presence of superoxide dismutase (SOD, 250 units/ml). 3. 3. Nitric oxide-generating agent, S-nitroso- N-acetylpenicillamine, caused the relaxation of aorta without endothelium in a concentration-dependent manner, and the concentration-response curve was shifted to the right in the presence of MMA C 60. This inhibitory effect of the derivative was also masked in the, presence of superoxide dismutase (SOD). 4. 4. Sodium nitroprusside-induced relaxation was not affected by either MMA C 60 or SOD. In the other tissues, this C 60 derivative had no effect on the responses induced by any agonist. 5. 5. These observations indicate that MMA C 60 inhibits the endothelium-dependent relaxation induced by acetylcholine but does not affect the agonist-induced contractile response of smooth muscle.

Inhibition of injury induced intimal hyperplasia by saralasin in rats

Increasing evidence points toward local production of renin and angiotensinogen in the artery wall. Because angiotensin converting enzyme (ACE) inhibitors have been shown to block intimal hyperplasia after arterial injury in the rat, it has been suggested that angiotensin II is an important mediator of the proliferative response to vascular injury. To prove that previous observations with use of ACE inhibitors are a result of effects on local angiotensin levels versus nonspecific drug effects, we tested the ability of an unrelated drug, the angiotensin II receptor antagonist saralasin, to similarly block intimal hyperplasia after aortic injury in the rat. Balloon catheter aortic denudation was performed in 28 rats pharmacologically treated for 14 days after surgery and split into four groups: group 1, saralasin 360 μg/kg/hr intravenously; group two, normal saline 0.5 mm3/hr intravenously; group 3, captopril 100 mg/kg/day orally; and group 4, heparin 50 U/kg/hr intravenously. Animals were killed and aortas were perfusion fixed at physiologic pressure 14 days after denudation. Cross-sectional intima-to-media ratios were calculated by computerized planimetry. Compared with saline controls, saralasin inhibited intimal hyperplasia 45% (p < 0.001), captopril 59% (p < 0.001), and heparin 68% (p < 0.001). A reduction in total intimal area was also evident in animals treated with saralasin (p < 0.01). Blood pressure in the group treated with captopril decreased from 107.4 ± 3.9 to 96.3 ± 4.3 mm Hg (p < 0.01) after 6 days, whereas saralasin and heparin had no effect on blood pressure. Weight gain during the study was reduced in groups treated with captopril and heparin but not in the group treated with saralasin. This work indicates that attenuating local angiotensin II effects both at the level of ligand production and receptor blockade interfere with the proliferative response to vascular injury. These results in combination with evidence of angiotensionogen production in the artery wall provide strong support for the hypothesis that angiotensin II induces smooth muscle cell proliferation after aortic injury in the rat.